The alkaloid camptothecin (CPT, 1) shows potent antiproliferative activity and continues to serve as a very attractive lead structure for the development of new anti-cancer drugs (see e.g. in C. J. Thomas, N. J. Rahier, S. M. Hecht, Bioorg Med Chem. 2004, 12, 1585-1604). The structure of the pentacyclic skeleton contains a highly electrophilic α-hydroxy-δ-lactone ring (ring “E”), which rapidly hydrolyzes in basic and neutral media yielding the open chain carboxylate form (2, scheme 1), which is almost inactive.

This equilibrium is shifted toward the carboxylate form in human plasma thus explaining the lower efficacy of most CPT analogues in clinical trials.
The development of homocamptothecins (hCPT), which are CPT analogues possessing a seven membered β-hydroxy-ε-lactone ring “E”, addressed this issue. Although it was previously generally accepted that an α-hydroxylactone is an indispensable structural feature for anticancer activity, modifications of the CPT-lactone ring which retain the antiproliferative activity and, at the same time, displays enhanced stability against hydrolysis were investigated (Lavergne, Bigg et al., J. Med. Chem. 2000, 43, 2285-2289). Therefore hCPT provides an excellent template for the preparation of new, highly cytotoxic compounds, and two promising hCPT derivatives, 3 (Difiomotecan) and 4 (scheme 2), are under investigation for the treatment of cancer.

Processes for the manufacture of hCPT's are known in the art (U.S. Pat. No. 6,723,853 B2) principally following the general synthesis route given in scheme 3, wherein “X” and “Y” represent optional substituents (see also Lavergne, Bigg et al., J. Med. Chem. 2000, 43, 2285-2289).

However, when used in large scale manufacture (kg-amounts) these processes suffer from an extremely low yield of typically 0.5% of the bicyclic “DE-fragment”, which is essential for the biological activity in the final product. Therefore it remains the need to provide alternative synthesis routes of this fragment.